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Thrombolytic therapy nearly halved mortality in patients with pulmonary embolism, but at the cost of a higher risk of major bleeding, especially in the elderly, a meta-analysis found.

The therapy was associated with a 47% reduction in mortality and a 2.7-fold increase in major bleeding compared with standard anticoagulant therapy in an analysis of studies conducted over the past 4 decades.

Major bleeding was not significantly increased in patients younger than age 65 (OR 1.25, 95% CI 0.50-3.14). This finding highlights the importance of assessing bleeding risk in elderly patients with intermediate-risk pulmonary embolism (PE) being considered for thrombolytic therapy, , of St. Luke's-Roosevelt Hospital Center in New York City, and colleagues wrote in the June 18 issue of .

The issue of whether thrombolysis improves survival in intermediate-risk PE patients has been a subject of debate for several decades, and the meta-analysis is the first with sufficient statistical power to detect a meaningful reduction in mortality. But the positive finding was tempered by an increased bleeding risk among the elderly, cardiologist Joshua A. Beckman, MD, noted in an interview with MedPage Today.

A subgroup analysis of patients over the age of 65 revealed a threefold increase in risk of major bleed in patients treated with thrombolytic therapy compared with anticoagulant therapy (OR 3.10, 95% CI 2.1-4.56, 12.93% [87/673] versus 4.10% [27/658]).

"This really makes everybody quite hesitant about the use of thrombolytic therapy in patients over the age of 65," Beckman said.

'Intermediate Risk' Patients in Some Trials

PE accounts for nearly 200,000 hospital discharges and 30,000 deaths each year in the U.S., according to .

Currently, the classification of patients into risk groups typically guides clinical decisions about whether thrombolytic therapy will be used. Patients presenting with right ventricular failure and hemodynamic compromise have a high risk for death and are generally considered candidates for the treatment, while further risk stratification may be needed in patients with stable blood pressure, Beckman wrote in an editorial published with the study.

He noted that for intermediate risk patients (defined as those who were hemodynamically stable with objective evidence of right ventricular dysfunction) with a relatively low risk of death, the value of thrombolytic therapy has been unclear.

The newly published meta-analysis included 16 randomized trials comparing thrombolytic therapy with anticoagulation therapy performed over the last 45 years, including eight trials with a total of 1,775 patients that specified inclusion of "intermediate-risk" patients.

The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding. Secondary efficacy and safety outcomes were risk of a recurrent PE and intracranial hemorrhage, respectively.

Among the findings:

• Thrombolytic therapy was associated with lower all-cause mortality (OR 0.53, 95% CI 0.32-0.88, 95% CI 31-380). A total of 2.17% of those in the thrombolysis group died, compared with 3.89% of those in the anticoagulant cohort, at a mean follow-up of 81.7 days.
• Thrombolytic therapy was associated with a greater risk of major bleeding compared with anticoagulant therapy (OR 2.73, 95% CI 1.91-3.91, 95% CI 13-27). There was a 9.24% rate of major bleeding in the thrombolytic therapy cohort, and a 3.42% rate in the anticoagulation cohort.
• Thrombolysis demonstrated an association with greater risk of intracranial hemorrhage (OR 4.63, 95% CI 1.78-12.04) and lower risk of recurrent PE (OR 0.40, 95% CI 0.22-0.74).
• In the subgroup analysis of patients ages 65 and older, there was a nonsignificant association with lower mortality (OR 0.55, 95% CI 0.29-1.05), and the previously mentioned threefold increase in major bleed risk.

In an analysis of the eight trials which identified intermediate-risk patients, associations with lower mortality were derived largely from use of thrombolytics in intermediate-risk PE patients treated between 2009 and 2014 (1.99% versus 4.02%, OR 0.39, 95% CI 0.19-0.82).

Beckman said the fact that the researchers had to go back more than 40 years to acquire the data they needed to conduct their analysis highlights the need for strong clinical trials assessing the risk and benefits of thrombolytic therapy in this patient population.

"Medical care today is nothing like medical care 40 years ago, and, in fact, there have been dramatic improvements in care through many different fields," he said. "I think the most obvious evidence for this has been in the decreasing rate of mortality over time in the studies that were included. So it is hard to make a complete judgment on this wonderfully done meta-analysis because the data have been acquired over such a long period of time."

Catheter-Directed Treatment

Just one small study included in the analysis -- the -- evaluated the use of catheter-directed thrombolysis, which limited its generalizability beyond patients receiving systemic treatment, the researchers wrote.

Beckman said catheter-directed therapy may prove to be a game-changer for the treatment of intermediate risk PE patients by reducing bleeding risk and improving treatment outcomes. He added that smaller and shorter clinical trials than were conducted in patients receiving systemic therapy may be needed to prove the usefulness of catheter-directed thrombolysis in intermediate-risk patients.

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